The complex response to allergen exposure results in a cascade of effects involving numerous mediators comprising different cell types like neutrophiles, monocytes, eosinophiles, mast cells and T helper (Th) cells as well as cytokines and chemokines. For example, Th2 cells regulate allergic responses by producing Th2 cytokines, such as interleukin (IL)-4, IL-5 and IL-13. Among the events triggered by such mediators are Th2 cell differentiation, immunoglobulin (Ig)E synthesis, mast cell growth and differentiation, upregulation of CD23 expression, differentiation, recruitment, migration and activation of effector cells, such as eosinophils and basophils as well as the priming for their prolonged survival. Allergic or immune responses due to sustained release of above-mentioned mediators may culminate, if untreated, in severe inflammatory diseases with end-organ damage, hyper-responsiveness, enhanced vascular permeability, edema, mucous hyper-secretion, airway hyperactivity, and bronchioconstriction.
Prostaglandin D2 (PGD2), histamine, cysteinyl leukotrienes (CysLTs) and thromboxane A2 (TxA2) are chemokines considered to act as proinflammatory key mediators in allergic responses. PGD2 is a major cyclooxygenase metabolite of arachidonic acid and is released in large amounts from activated mast cells during allergic attacks.
PGD2 is known to activate thromboxane A2 (TP) receptor, PGD2 (DP1) receptor and recently identified G-protein-coupled “chemoattractant receptor-homologous molecule expressed on Th2 cells” (CRTH2 or DP2) receptor. CRTH2 receptors are expressed on Th2 cells, eosinophiles and basophiles. PGD2 induces migration and activation of these cells via CRTH2 receptor activation.
A plethora of medications, such as anti-histamines, β2-agonists, leukotriene modifiers, non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors, immunosuppressants, and monoclonal anti-IgE antibody have been used to treat symptoms of allergic conditions. Corticosteroids remain the most effective medication in the treatment of allergen-induced disorders, despite severe dose-limiting side effects that are due to non-specific inhibition of the transcription of several cytokines and chemokines. Such medications do not cure the disease and debilitating symptoms may relapse soon after treatment is stopped. Thus, there is still a need for new modalities to treat and/or to prevent allergic responses by suppressing specifically chemoattractant induced, e.g. PGD2 induced, tissue invasion of effector cells. Therefore, antagonists blocking CRTH2 receptor binding of PGD2 should be useful for the treatment of allergic conditions.
So far, few compounds having CRTH2 antagonistic activity have been reported in the patent literature. Bayer AG claims in GB Patent Specification No. 2388540 the use of Ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid) for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjuvatitis. Oral bioavailability of Ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported in Journal of Pharmacology and Experimental Therapeutics, 2003, 305(1), 347-352.